ABSTRACT: Despite gains made in symptomatic therapies for Parkinson Disease (PD), disease-modifying trials have not been successful. Discovering genetic biomarkers that identify heterogeneity among disease states and subgroups facilitates logistics of trial design and inspires targets for intervention. Several lines of evidence indicate that current classification schema using PD single gene subgroups only are inadequate and do not fully reflect the spectrum of clinical etio-pathology, including growing evidence for oligogenic mechanisms. Thus there is a need to identify additional genes and contributing genetic biomarkers. These may help in the development of a composite score, similar to practice in oncology whereby multiple genetic risk factors are assessed in therapeutic decision-making.. Herein, we strive to elucidate blood-based genetic biomarkers through evaluation of individuals of Ashkenazi Jewish (AJ) background. In addition to a higher rate of PD and increased frequency of LRRK2 and GBA mutations, these individuals are characterized by genetic homogeneity and founder effects that may facilitate elucidation of disease-related genes with much smaller sample sizes. This is now a pivotal moment in PD disease modifying trials as agents directed at GBA related targets and LRRK2 mediated therapies are either underway or in planning. In Aim 1 we will enroll AJ PD with LRRK2 G2019S mutations, GBA mutations and no mutations, as well as non-manifesting gene carriers, and non-disease non-mutation controls. This aim will provide precious samples as resource for the Parkinson Disease Biomarker Program (PDBP) and thus the community, and DNA and RNA for Aims 2 and 3. In Aim 2 we will perform genomic analysis to evaluate pathways implicated in PD. These include genes related to a) PD and movement disorder-related overlap syndromes, b) lysosomal storage disorders, and c) immune processes. This aim is primarily exploratory but has great potential as mutations readily identified in this population, such as GBA, have worldwide disease significance. In Aim 3, our central hypothesis is that the transcriptome of peripheral monocytes harbors important functional variation that underlies the pathobiology of PD directly or reflects variation in expression in myeloid cells within the brain, such as microglia, and will evaluate profile gene expression from specific immune cells. Aim 2 will provide WGS and Aim 3 RNASeq data for the community. We will use state-of the art bioinformatics techniques to evaluate genomics and transcriptomics within and across the aims. The translational potential is that blood-based biomarkers could be readily assayed in the clinic and could also give individual information about subtype of disease thereby enabling direct study of new targets and improved clinical trial design and likelihood of success. Taken together, this approach holds great potential for better understanding PD pathogenesis, including illuminating disease pathways and providing biomarkers to understand heterogeneity, leading to improved clinical trials and personalized disease modifying therapies for PD. !